Ribosome ADP-ribosylation inhibits translation and maintains proteostasis in cancers.

Defects in translation lead to changes in the expression of proteins that can serve as drivers of cancer formation. Here, we show that cytosolic NAD+ synthesis plays an essential role in ovarian cancer by regulating translation and maintaining protein homeostasis. Expression of NMNAT-2, a cytosolic NAD+ synthase, is highly upregulated in ovarian cancers. NMNAT-2 supports the catalytic activity of the mono(ADP-ribosyl) transferase (MART) PARP-16, which mono(ADP-ribosyl)ates (MARylates) ribosomal proteins. Depletion of NMNAT-2 or PARP-16 leads to inhibition of MARylation, increased polysome association and enhanced translation of specific mRNAs, aggregation of their translated protein products, and reduced growth of ovarian cancer cells. Furthermore, MARylation of the ribosomal proteins, such as RPL24 and RPS6, inhibits polysome assembly by stabilizing eIF6 binding to ribosomes. Collectively, our results demonstrate that ribosome MARylation promotes protein homeostasis in cancers by fine-tuning the levels of protein synthesis and preventing toxic protein aggregation.

Micro-RNAs associated with the evolution of ovarian cancer cisplatin resistance.

OBJECTIVES: Ovarian cancer (OVCA) is the leading cause of mortality among women with gynecologic malignancy, in part due to the development of chemoresistance. We sought to identify micro-RNAs (miRNAs) associated with in vitro development of OVCA chemoresistance that may also represent potential targets for therapy. METHODS: In this study, four OVCA cell lines (A2780CP, A2780S, IGROV1, and OVCAR5) were serially treated with cisplatin in parallel with measurements of miRNA expression changes. RESULTS: Nine miRNAs were found to be associated with increasing cisplatin resistance (IC50) (p<0.01); however, only 5 of these miRNAs have publically available information. Pathway analysis identified 15 molecular signaling pathways that were represented by genes predicted to be targets of the 5 miRNAs (false discovery rate<0.05), 11 of which are associated with the epithelial-mesenchymal transition (EMT). Further analysis identified 2 of those pathways as being associated with overall survival in 218 patients with OVCA. CONCLUSIONS: Collectively, this panel of miRNAs associated with in vitro evolution of OVCA cisplatin resistance and the pathways identified to be associated with EMT and overall patient survival provide a framework for further investigations into EMT as a therapeutic target in patients with OVCA.

The Chinese herb polyphyllin D sensitizes ovarian cancer cells to cisplatin-induced growth arrest.

PURPOSE: We evaluated the effects of polyphyllin D (PD), a natural compound with anti-neoplastic activity and a major component of the Chinese herb Paris polyphylla, on ovarian cancer (OVCA) cell line proliferation and platinum sensitivity. METHODS: A panel of 20 OVCA cell lines was subjected to PD treatment, MTS proliferation assays, and determination of IC50. Pre-treatment, baseline genome-wide Affymetrix expression analysis was performed on each cell line, and Pearson's correlation was performed to identify genes associated with OVCA PD sensitivity. Twelve cell lines were treated with PD with and without cisplatin, and the effects of PD on cisplatin IC50 were quantified. Genes associated with OVCA PD sensitivity were evaluated for associations with survival in a publically available clinico-genomic dataset of 218 patients with OVCA. RESULTS: Our results showed that PD exhibited anti-proliferative effects against all OVCA cell lines tested, with IC50 values ranging from 0.2 to 1.4 µm. Furthermore, in all cell lines, PD treatment significantly decreased cisplatin IC50 (mean IC50 reduction of 2.1 µm; P < 0.02). Pearson's correlation test identified 25 probe sets, representing 18 unique genes to be associated with PD sensitivity (FDR = 0). We found that one of these genes was associated with overall survival in women with OVCA: CLDN4 (P = 0.014). CONCLUSION: Our findings highlight the value of PD as a natural product with anti-cancer properties, which may also enhance the activity of existing therapeutic agents.

A ten year experience of cecal neovagina procedures for the restoration of sexual function on a gynecology oncology service.

OBJECTIVE: We seek to describe the procedure, complications, and functional outcomes of utilizing the cecum and ascending colon for creation of a neovagina on a gynecologic oncology service. METHODS: A search of all the cases on the gynecologic oncology service over a ten year period yielded fourteen cases of cecal neovagina. A retrospective chart review was performed. Post-operatively, each patient was evaluated at regular intervals. At each visit, they were asked standardized questions, a physical exam was performed by the same provider, and they were advised to follow a uniform regimen of physical rehabilitation. RESULTS: Eight of the fourteen cases were performed for surgical stricture or vaginectomy, while the indication for the other six patients was radiation fibrosis. The patients were followed for a median length of 37 months. The percentage having intercourse was between 86% and 100% over the course of the first year. Thirteen of the fourteen patients reported intercourse as "comfortable", eleven of the fourteen stated that intercourse was "pleasurable", and seven patients reported having orgasms. The major reported complaint was mucusy discharge, which all patients reported as moderate to severe for the first six weeks. Over time, this improved, and only one patient required the use of pads at twelve months. There were no intestinal anastomotic leaks in the group. CONCLUSIONS: The functional outcomes in our case series show that the cecal neovagina is a safe, uncomplicated, and viable option for those patients who have lost sexual function due to stricture formation or surgical removal of the vagina.

Dietary intake and ovarian cancer risk: a systematic review.

Ovarian cancer is a leading cause of gynecological cancer death. There is a need to identify modifiable dietary risk factors for this disease. To evaluate the role of diet in ovarian cancer risk, we performed a PRISMA-directed systematic review that included prospective cohort studies with >200 cases (n = 24). Higher risk for ovarian cancer was shown for total, animal, and dairy fat (five of nine studies), as well as total nitrate and possibly total vitamin C. No associations were demonstrated for red meat, fiber, vitamin A, vitamin E, ß-carotene, or folate. Vegetables were associated with lower risk in one of three studies; fruit showed no association, although risk estimates were all greater than 1.0. Isoflavones and flavonoids were associated with modestly lower risk in two studies and tea intake was associated with lower risk in one of two studies. This review suggests that no specific dietary factors are consistently associated with ovarian cancer risk. Data by tumor subtypes are limited, but suggest that differential associations by tumor subtype may exist and should be evaluated. Studies of ample sample size, varied exposure, which can better control for dietary measurement error, are needed to fully define dietary recommendations for ovarian cancer prevention.